Naturally occurring genetic differences and molecular genetic manipulations of the genome provide a means for investigating the neurobiology and psychopharmacology of abused drugs. Our laboratory is specifically interested in the integration of molecular biology, behavior genetics and behavior pharmacology as a tool to investigate the neurobiological mechanisms in vulnerability to drug abuse. The goal of the experiments described herein has been to identify neural regions significantly associated with the efficacy of morphine as a reinforcer and to determine potential commonalties across other drugs of abuse. To date, our laboratory has examined intravenous opioid self-administration behavior in four inbred rat strains and several inbred, recombinant inbred and transgenic lines of mice. The genetic relationship across simple (Fixed Ratio) and more demanding (Progressive Ratio) schedules of reinforcement has been determined in all these genotypes. Multivariate analysis of the relationship between genetic differences in the neuroanatomical distribution of |-opiate receptor concentration and preproenkephalin mRNA and the relative potency and efficacy of opioid reinforced behavior has been used as a means to suggest potential neural regions associated with vulnerability to opioid drug abuse. Results of these studies demonstrate that 1) The genotype of the subject significantly affects the efficacy of morphine as a reinforcer, 2) Genotype significantly affects the concentration and regional distribution of mu-opiate receptors and preproenkephalin, 3) No one region can account for the genetic variance seen in morphine self-administration behavior and 4) Relative sensitivity to the locomotor stimulant or analgesic effects of morphine are not predictive of drug self-administration behavior whereas the conditioned locomotor stimulant effects of the drug may be predictive of behavior under the progressive ratio schedule of reinforcement. Additional studies have been established to determine the relative level of nicotine and cocaine self-administration behavior across some of these same genotypes. Initial results suggest that nicotine and cocaine will serve as a positive reinforcer in a mouse genotype that readily self- administers morphine. These studies will help to identify potential neurobiological mechanisms common across drugs of abuse.